Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration. Protein kinases also play specialized roles in a host of human diseases like transplant rejection, rheumatoid arthritis, psoriasis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematologic malignancies such as leukemias and lymphomas. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Cytokine-stimulated immune and inflammatory responses contribute to pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune/inflammatory response contributes to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000) Arthritis Res 2(1): 16-32) Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription (STATs). Janus kinase (JAK) is a family of intracellular non-receptor tyrosine kinases, ranging from 120-140 kDa, that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. Currently, there are four known mammalian JAK family members: JAK 1, JAK 2, JAK 3 and TYK 2. JAK 1, JAK 2 and TYK 2 are ubiquitously expressed whereas JAK 3 is expressed in the myeloid and lymphoid lineages.
Vandeghinste et al. (WO 2005/124342) discovered JAK1 as a target whose inhibition might have therapeutic relevance for several diseases including OA. Knockout of the JAK1 gene in mice demonstrated that JAK1 plays essential and non-redundant roles during development.
JAK2 is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the gamma-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. Studies have disclosed an association between an activating JAK2 mutation (JAK2V617F) and myleoproliferative disorders. The myeloproliferative disorders, a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythroid, megakaryocyte, or monocyte lineage cells. Myeloproliferative disorders (MPD) include polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), juvenile myelomonocytic leukemia (JMML) and systemic mast cell disease (SMCD). It has been suggested that abnormalities in signal transduction mechanisms, including constitutive activation of protein tyrosine kinases, initiate MPD. Jak2−/− mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis.
JAK3 associates with the common gamma chain of the extracellular receptors for the following interleukins: IL-2, IL-4, IL-7, IL-9 and IL-15. A JAK3 deficiency is associated with an immune compromised (SCID) phenotype in both rodents and humans. The SCID phenotype of JAK3 (−/−) mammals and the lymphoid cell specific expression of JAK3 are two favorable attributes of a target for an immune suppressant. Data suggests that inhibitors of JAK3 could impede T-cell activation and prevent rejection of grafts following transplant surgery, or to provide therapeutic benefit to patients suffering autoimmune disorders. An important feature of JAK3 is that it specifically associates with the common cytokine receptor gamma chain which is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Unlike the other JAK family members that are more widely expressed in many mammalian tissues, JAK3 expression seems to be mainly limited to the endoplasmic membranes of hematopoietic cells. JAK3 is validated by mouse and human genetics as an immune-suppression target (O'Shea J. et al. (2004)). JAK3 inhibitors were successfully taken into clinical development, initially for organ transplant rejection but later also in other immuno-inflammatory indications such as rheumatoid arthritis (RA), psoriasis and Crohn's disease.
Blocking signal transduction at the level of the JAK kinases holds promise for developing treatments for human cancers and arthritis. Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In view of numerous conditions that are contemplated to benefit by treatment involving modulation of JAK pathways it is immediately apparent that new compounds that modulate JAK pathways and method of using these compounds should provide substantial therapeutic benefit to a wide variety of patients.
Patent applications from Portola (WO 2010/129802, WO 2009/145856, WO 2009/136995 etc.) discloses pyrimidine class of compounds as Spleen Tyrosine Kinases (SYK) or JAK inhibitors.

Rigel has filed a number of patent applications (WO 2011/017178, WO 2010/085684, WO 2010/078369, WO 2010/075558 and WO 2010/039518 etc.) claiming pyrimidine class of compounds as useful modulators of JAK pathways or as inhibitors of JAK kinases particularly JAK-2, JAK-3 or both.

Avila Therapeutics reported pyrimidine class of compounds as protein kinase inhibitors (WO 2010123870, WO 2009/158571, WO 2009/051822 and WO 2008/151183).

Cytopia Research Pvt. Ltd reported phenyl amino pyrimidine class of compounds as protein kinase inhibitors including JAK (WO 2008109943, WO 2009029998).

Cytopia reported following two compounds in their patent application WO 2008109943. The reported in vitro JAK 2 and JAK-3 inhibition for compounds 2 is less than 1 μM and less than 20 μM respectively.

However, none of these compounds have reached the market and keeping in mind the huge unmet potential for such molecules, there is a need to develop compounds which modulate the JAK enzymes in a therapeutically effective way. We herein below disclose such novel molecules.